MALE INFERTILITY : MALE INFERTILITY DR. Muhammad Ishfaq
Postgraduate resident in urology & transplant,
Institute of kidney diseases, hmc, Peshawar
July 2010 DEDICATION : DEDICATION TO freedom flotilla CONTENTS : CONTENTS DEFINITION
ANATOMY AND PHYSIOLGY
TREATMENT Definition of Infertility : Definition of Infertility The couple has not conceived after 12 months of contraceptive-free intercourse if the female is under the age of 34. 12 months is the lower reference limit for Time to Pregnancy (TTP) by the World Health Organization.1
The couple has not conceived after 6 months of contraceptive-free intercourse if the female is over the age of 35 (declining egg quality of females over the age of 35 account for the age-based discrepancy as when to seek medical intervention
Makar RS, Toth TL (2002). "The evaluation of infertility". Am J Clin Pathol. 117 Suppl: S95–103. PMID 14569805. Slide 6: Male factor– 20%
May extend from 30-40%, as contributory factor Slide 7: EMBRYOLOGY AND GENETICS Sexual Differentiation: Internal Embryonic Development : Sexual Differentiation: Internal Embryonic Development Sexual Differentiation: External Genitalia : Sexual Differentiation: External Genitalia Pathway for Sexual Development: Review for Genes to Organs : Pathway for Sexual Development: Review for Genes to Organs Slide 11: Human y chromosome has SRY region HISTOLOGY : HISTOLOGY TESTIS: CROSS SECTION : TESTIS: CROSS SECTION SEMENIFEROUS
TUBULE SERTOLI CELLS SPERMATAZOON TESTIS: THE MALE GONAD : TESTIS: THE MALE GONAD SEMENIFEROUS
TUBULE RETE TESTIS VAS DEFERENS EFFERENT
DUCTULES EPIDIDYMIS PHYSIOLOGY : PHYSIOLOGY REGULATION OF H-P-T AXIS : REGULATION OF H-P-T AXIS MALE REPRODUCTION: HORMONAL REGULATION : MALE REPRODUCTION: HORMONAL REGULATION HYPOTHALAMUS GONADOTROPIN RELEASING HORMONE ANTERIOR PITUITARY TESTES FSH LH S
CELL LEYDIG CELL TESTOSTERONE INHIBIN REP.TRACT
& OTHER ORGANS SPERMATOGENESIS - ve feedback - ve feedback SPERMATOGENESIS : SPERMATOGONIA (DIPLOID) PRIMARY
(DIPLOID) MITOSIS SPERMATOGENESIS SPERMATOGENESIS Contd. : SPERMATOGENESIS Contd. PRIMARY SPERMATOCYTES SECONDARY SPERMATOCYTES
(HAPLOID) MEIOSIS I SPERMATIDS (HAPLOID) SPERMATOZOA (HAPLOID) MEIOSIS II SPERMIOGENESIS Slide 20: SEMINIFEROUS TUBULE Testis:
macrophages, endothelial cells Sertoli cells : Sertoli cells Form blood-testes barrier:
Prevents autoimmune destruction of sperm.
Produce FAS ligand which binds to the FAS receptor on surface to T lymphocytes, triggering apoptosis of T lymphocytes.
Prevents immune attack.
Phagocytize residual bodies:
May transmit information molecules from germ cells to Sertoli cells.
Secrete androgen-binding protein (ABP):
Binds to testosterone and concentrates testosterone in the tubules. Blood –testes barrier : Blood –testes barrier Slide 23: Spermiogenesis Sperm : Sperm Slide 25: sperm
55-65 µm in length
Three parts head, neck and tail. On the outside of the anterior two thirds of the head is a thick cap called the acrosome that is formed mainly from the Golgi apparatus.
It contains enzymes similar to those found in lysosomes hyaluronidase and powerful proteolytic enzymes. These play important roles in allowing the sperm to enter the ovum and fertilize it. Sperm : Sperm The tail of the sperm, called the flagellum, has three
(1) A central skeleton constructed of 11 microtubules, collectively called the axoneme
(2) A thin cell membrane covering the Axoneme
(3) A collection of mitochondria surrounding the axoneme in the proximal portion of the tail (called the body of the tail)
Normal sperm move in a fluid medium at a velocity
of 1 to 4 mm/min. SPERM TRANSPORTATION : SPERM TRANSPORTATION Sperm motility : Sperm motility Grading is as follows:
Grade 0 is no movement,
Grade 1 is sluggish movement,
Grade 2 is slow movement but not straight,
Grade 3 is movement in a straight line, and
Grade 4 is terrific speed.
Patients with abnormal motility should be evaluated for pyospermia, antisperm antibodies, varicocele, sperm ultrastructural abnormalities, or partial ductal obstruction. Contribution in semen formation : Contribution in semen formation Testes …sperms (3 to 5%)
Epidydimis…maturation of sperms,phosphorylcholine,carnitine,sialic acid.
Vas deference.. conduit,absorptive and secretive properties .
Seminal vesicle.( 40 to 80%of ejaculate) fructose for sperm nutrition, prostaglandins and other coagulating substances, and bicarbonate to buffer the acidic vaginal vault.
Prostate ..(10----30% of ejaculate ) enzymes and proteases to liquefy the seminal coagulum. This usually occurs within 20-25 minutes. The prostate also secretes zinc, phospholipids, phosphatase, and spermine
Bulbourethral &periurethral gland, (2 to 5 % each).lubricate and buffer residual urine. ETIOLOGY : ETIOLOGY Etiology of male infertility : Etiology of male infertility PRETESTICULAR
POST TESTICULAR PRE-TESTICULAR : PRE-TESTICULAR HYPOTHALAMIC DISEASES
ISOLATED LH DEFECIENCY
ISOLATED FSH DEFECIENCY
CONGENITAL HYPOGONADOTROPIC SYNDROME
Ejaculatory failure TESTICULAR : TESTICULAR Bad semen quality
Klienfelter syndrome, Y chromosome deletion,
Immotile cilia syndrome
IDIOPATHIC POST TESTICULAR : POST TESTICULAR OBSTRUCTIVE
ACCESSORY GLAND INFECTION
Infertility is also thought to be passed on to the son from the father. FREQUENCY OF ETIOLOGIES : FREQUENCY OF ETIOLOGIES HOW TO APPROACH ? : HOW TO APPROACH ? EVALUATION OF INFERTILITY (MALE) : EVALUATION OF INFERTILITY (MALE) HISTORY
70% cases are detected with these GENERAL EXAMINATION : GENERAL EXAMINATION Height
Secondary sexual character LOCAL EXAMINATION : LOCAL EXAMINATION Scrotal volume (N=15-35ml)
Testicular volume (N=15-25ml)
Presence of varicocele
P/R examination Semen analysis : Semen analysis Gland Approximate %Description : Gland Approximate %Description Testes
2-5%Approximately 200- to 500-million spermatozoa produced in the testes, are released per ejaculation.
65-75%amino acids, citrate, enzymes, flavins, fructose (the main energy source of sperm cells, which rely entirely on sugars from the seminal plasma for energy), phosphorylcholine, prostaglandins (involved in suppressing an immune response by the female against the foreign semen), proteins, vitamin C
25-30%acid phosphatase, citric acid, fibrinolysin, prostate specific antigen, proteolytic enzymes, zinc (serves to help to stabilize the DNA-containing chromatin in the sperm cells. A zinc deficiency may result in lowered fertility because of increased sperm fragility. Zinc deficiency can also adversely affect spermatogenesis.)
< 1%galactose, mucus (serve to increase the mobility of sperm cells in the vagina and cervix by creating a less viscous channel for the sperm cells to swim through, and preventing their diffusion out of the semen. Contributes to the cohesive jelly-like texture of semen.), pre-ejaculate, sialic acid Slide 43: © Oozoa Biomedical Inc, April 2005 Diagnosis of sterility
Diagnosis of infertility
Prognosis for fertility
Identify treatment options:
assisted conception treatment
Therefore = a screening test to help direct management. WHY PERFORM SEMEN ANALYSIS? Semen analysis : Semen analysis It is not measure of fertility. One source states that 30% of men with a normal semen analysis actually have abnormal sperm function 1
An abnormal test suggest likelihood of decreased fertility.
There are certain limits below which it is not statistically possible to initiate pregnancy.
Of these sperm count and motility correlate best with fertility.
"Understanding Semen Analysis". Stonybrook, State University of New York. 1999. http://www.uhmc.sunysb.edu/urology/male_infertility/SEMEN_ANALYSIS.html. Retrieved 2007-08-05 Semen collection : Semen collection Period of exual abstinence 48-72 hours. why ?
Sperm motility tends to fall when abstinence period is more then 5 days.
2 semen analysis
Self stimulation,coitus interuptus(less ideal), special condoms.
Analysis within one hour.
During transit body temperature. Slide 46: SEMEN ANALYSIS Semen Parameters Normal range (WHO)
Volume (1.5-5.5 ml)
Sperm density (>20 million/mL)
Sperm motility (>50%)
Forward progression 2(scale 1-4)
Sperm morphology (>30% normal forms)
>4% Kruger normal Leukocyte density (<1 million/mL)
Viscosity <3(scale 0-4)
Immunobead/MAR <10% coated Sperm parameter reminder : Sperm parameter reminder Azoospermia= absent sperm
Oligospermia= < 20 mio/cc
Asthenospermia= < 50% motility
Teratospermia= < 30% normal sperm (WHO) = < 6% normal sperm (Kruger morphology)
Main Causes of Decreased Parameters
15 % (azoo),
5 % (oligo)•
De novo del of azoosp factor region (AZF)
Cong. Bilat. Abs. of vas deferens (CBAVD)
1-2% (azoo) ABNORMALITIES : ABNORMALITIES Low ejaculate volume
Necrozoospermia Slide 49: Classification of Male Infertility Status by Criteria of Semen Analysis
I. Low Ejaculate Volume
B. Retroperitoneal or bladder neck surgery
C. Ejaculatory duct obstruction
D. Diabetes mellitus
E. Spinal cord injury
F. Psychologic disturbances
H. Incomplete collection
A. Hypogonadotropic hypogonadism
1. Kallmann syndrome
2. Pituitary tumor
B. Spermatogenic abnormalities
1. Chromosomal abnormalities
2. Y-chromosome microdeletions
5. Viral orchitis
C. Ductal obstruction Slide 50: III. Oligoasthenoteratospermia (OAT)
D. Drugs, heat, toxins
E. Systemic infection
IV. Normal But Infertile
A. Gynecologic abnormality
B. Abnormal coital habits
C. Acrosomal defects
D. Antisperm antibodies
A. Spermatozoal structural defects
B. Prolonged abstinence
D. Genital tract infection
E. Antisperm antibodies
G. Partial obstruction Computer-aided semen analysis (CASA) : Computer-aided semen analysis (CASA) Apart from previous mentioned,CASA can detect:
curvilinear velocity, defined as the average distance per unit time between successive sperm positions.
The straight-line velocity, which is the speed of forward direction.
linearity, which is the straight-line velocity divided by the curvilinear velocity
for research purposes. Absent or low ejaculate : Absent or low ejaculate Slide 53: ABSENT OR LOW EJACULATE VOLUME RULE OUT INCOMPLETE COLLECTION AND SHORT ABSTINENCE PERIOD POST EJACULATRY URINALYSIS RETROGRADE EJACULATION SYMPATHOMIMETICS/BLADDER WASH/AIH +VE -VE TRANSRECTAL ULTRASOUND PTO Slide 54: ABSENT OR LOW EJACULATE SEMINAL VESICAL ASPIRATION EJACULATORY DUCT OBSTRUCTION TURED & EPIDYDIDEMOVASOSTOMY SYMPATHOMIMETIC/ELECTROEJACULATION FAILURE OF EMISSION TURED EJACULATORY DUCT &EPIDYDIMAL OBSTRUCTION TRANSRECTAL ULTRASOUND NORMAL ABNORMAL +VE -VE Azoospermia : Azoospermia Slide 56: AZOSPERMIA CFTR testing Bilateral vasal agenesis MESA/IVF/AID
adoption Testis size Vasa present Vasa absent FSH Hypogonadotrophic
hypo gonadism FSH Testicular failure LH/Prolactin/CT
MRI,gonadotropins Normal/unilateral atrophy Bilateral atrophy TESE/IVF/AID
adoption high low Next slide Slide 57: azoospermia 57 Obstruction TESE/IVF/AID
adoption Testicular failure CONTD Epidyidomovasostomy
vasovasostomy Testicular biopsy FSH Normal Abnormal Asthenospermia : Asthenospermia Slide 59: ASTHENOSPERMIA Viability assay Ultrastructural defects/IVF/ICSI R/O HEAT,VARRICOCEL
Systemic illness,pyospermia ANTISPERM ANTIBODIES IMMUNOSUPRESION/ART MOTILITY +VE -VE >5% Electron microscopy <5% high low TRUS NEXT SLIDE Slide 60: ASTHENOSPERMIA CONTD: SEMINAL VESICAL ASPIRATION EJACULATORY DUCT OBSTRUCTION R/O HEAT,VARRICOCEL
Systemic illness,pyospermia TRUS TURED NORMAL ABNORMAL +VE Hormonal study : Hormonal study HORMONAL STUDY : HORMONAL STUDY Indications :
Sperm densities <10millions/ml
Evidence of impaired sexual function(impotence,libido).
Examination finding suggestive of endocrinopathy(eg thyroid).
On initial testing 10% of infertile male will have an abnormal hormone level with clinically significant endocrinopathy in 2 % of men Hormonal study : Hormonal study Serum FSH
The combination of tests will detect 99% endocrine abnormalities.
Testesterone reflects overall endocrine balance.FSH reflects more on sperm production.
Serum LH & Prolactine if teststerone & FSH are abnormal. Hormonal study : Hormonal study Plasma estradiole for underandronized male.
LFTs &TFTs ,RBS etc if there is any evidence of disease. Hormonal status in clinical Dx : Hormonal status in clinical Dx ↑ Slide 66: © Oozoa Biomedical Inc, April 2005 (2000) The WHO and Structured Management Slide 67: © Oozoa Biomedical Inc, April 2005 RESEARCH & NEW TECHNIQUESSperm kinematics The way sperm swim affects their fertility
To get through the cervix, they have to swim in a straight path
To get through the outer layer of the egg, they have to generate a lot of power – this is seen as hyperactivated motility Slide 68: Genetic Evaluation Karyotype analysis
Abnormal karyotype in ~3-5% of infertile men
Klinefelter’s (47 XXY); 1-2% of infertile men
Y- chromosome micro-deletions
7-10% of infertile men vs. ~2% of fertile men
Cystic Fibrosis (CF) gene mutations
~80% in CBAVD vs. ~30% of infertile vs. ~4% fertile men
Pryor et al, 1997, Oates et al, 1992, Mak & Jarvi, 1997
Genetic evaluation is recommended in all infertile men with severe
semen parameters in order to assess and prevent possible iatrogenic transmission of genetic mutations OTHER INVESTIGATIONS : OTHER INVESTIGATIONS Fructose content of seminal fluid (If absent-Congenital absence of seminal vesicle, Partial duct obstruction, Both)
Post coital test
Acrosome reaction assay
Urine for sperm 2nd line investigations : 2nd line investigations Semen leukocyte analysis
Anti sperm antibodies test
Hypoosmotic swelling test
Sperm penetration assay
Sperm chromatin structure
Y-chromosome microdeletion analysis Radiological testing : Radiological testing Scrotal ultrasound
Testes biopsy & vasography
FNA mapping of testes
Semen culture Testicular biopsy : Testicular biopsy Azoospermic men
with a normal-sized testis and normal fTindings on hormonal studies ;
To evaluate for ductal obstruction,
To further evaluate idiopathic infertility, and
To retrieve sperm.
For testicular biopsy include ruling out partial obstruction in patients with severe oligospermia.
Evaluating patients with hypogonadotropism to select those likely to respond to gonadotropin replacement, and
Retrieving spermatozoa in azoospermic patients undergoing IVF or ICSI Treatment : Treatment Assess Expectations for Male Infertility Treatment : Assess Expectations for Male Infertility Treatment What treatments were previously recommended? Were they followed correctly? What results were obtained? GENERAL TREATMENT : GENERAL TREATMENT Education- coital frequency and timing
Avoidance of substance/drug abuse
Avoidance of hot bath/tight underwear
Avoidance of horse riding, cycling GENERAL TREATMENT : GENERAL TREATMENT Diet
A diet high in antioxidants such as vitamin C and vitamin E has been proposed to improve the quality of sperm by decreasing the number of free radicals that may cause membrane damage.
Additionally, the use of zinc, fish oil, and selenium has been shown to be of benefit in some studies.
Patients should limit the use of potentially spermatotoxic substances such as cigarettes, marijuana, and anabolic steroids. Environmental exposures to harmful substances and/or conditions should be minimized.
The optimal timing to perform intercourse for conception is every 2 days at mid cycle.
The use of spermatotoxic lubricants should be avoided. Medications : Medications Testosterone (Andro-LA, Androderm, Delatestryl, Depo-Testosterone)
Clomiphene (Clomid, Serophene)
Menotropins (Pergonal, Repronex)
Stimulate spermatogenesis. Contain 75 IU of FSH and 75 IU of LH per vial.
Human chorionic gonadotropin (Novarel, Profasi, Pregnyl) PRETESTICULAR(ENDOCRINE).. : PRETESTICULAR(ENDOCRINE).. Hypogonadotropic hypogonadism-
Pulsatile GnRh, hCG, hMG, Testosteron, Clomiphen citrate, Tamoxifen
IVF/ICSE, Donor sperm, Adaptation
Androgen, FSH, Clomiphen
Strict control of DM, Hypothyroid PRETESTICULAR : PRETESTICULAR COITAL DISORDERS
PDE5 Inhibitor (Sildenafil)
Retrograde ejaculation, Neurogenic impotence,
Intrauterine insemination (IUI)
For ejaculatory problems phenylephrin or imipramine may be tried POST TESTICULAR.. : POST TESTICULAR.. Prior vasectomy (most common cause)
microsurgical vasovasostomy (better if less than 5 years)
Epididymal or vasal obstruction
-ICSI TESTICULAR.. : TESTICULAR.. Cryptorchidism-
Orchidopexy at 2-3 year of age
High ligation of internal spermatic
Surgical retrieval of spermatozoa,
followed by ICSI Obstructive Azoospermia (OA):Management Options : Obstructive Azoospermia (OA):Management Options Reconstructive surgery (vasal, epididymal)
Resection of ejaculatory duct (cyst)
Sperm retrieval from site proximal to obstruction
Genetic counseling for CF patients Management of NOA (I) : Management of NOA (I) Hypogonadotropic hypogonadism
Initial 1,000-2,500 IU HCG (x2/wk) followed by 75-150 IU HMG (x3/wk) (Finkel,1987)
Combination of HCG and HMG (Yong ,1997)
GnRH sc or pulsatile infusion (Kliesch,1994)
LHRH pulsatile treatment (Shargil,1987)
IHH after puberty showed better results.
Sperm count increase in 3-6mos. Management of NOA (II) : Management of NOA (II) Varicocelectomy
Mehan DJ (1976, Fertil Steril)
Of 10 azoo men, 2 with varicocele results in pregnency
Matthews G, et al (1998, Fertil Steril)
Of 22 with azoo, sperm recovery rate is 55%
Kim ED, et al (1999, J Urol)
Of 28 men, 12(43%): mean post-op sperm count 1.2x106 /ml
Indication: severe hypospermatogenesis,
MA spermatid stage Management of NOA(III) : Management of NOA(III) ICSI
less invasive,cost effective
HH, varicocele, mosaic Klinfelter’s synd.
Presence of spermatozoa in SCO, MA
Nonmosaic Klinfelter’s syndrome (Bourne,1997 , Hum Reprod)
MA spermatid stage Assisted Reproduction Technology : Assisted Reproduction Technology What is ART? : What is ART? Group of high tech treatment methods to improve infertility.
In Vitro Fertilization
Gamete Intra-Fallopian Transfer
And many more ART Treatments for Infertility : ART Treatments for Infertility American Society for Reproductive Medicine. 2003.
American Society for Reproductive Medicine. 2001. IVF with embryo transfer Gamete intrafallopian transfer (GIFT) Zygote intrafallopian transfer (ZIFT) Cryopreservation Intracytoplasmic sperm injection (ICSI) Louise Brown : Louise Brown On July 25, 1978, Louise Joy Brown, the world's first successful "test-tube" baby was born in Great Britain. History of ART : History of ART 1978- first successful birth using In Vitro Fertilization
1984- first successful birth using Gamete Intra Fallopian Transfer
1986-first successful birth using Zygote Intra Fallopian Transfer Methods of sperm retrieval : Methods of sperm retrieval MESA
TESA IVF with Embryo Transfer : IVF with Embryo Transfer Egg and sperm are retrieved from couple, donor(s), or both Combined in a petri dish, incubated for 2–5 days If fertilization and cleavage occurs, embryo is transferred through a catheter to uterus Gamete Intrafallopian Transfer (GIFT) : Gamete Intrafallopian Transfer (GIFT) Oocytes retrieved via laparoscopy Oocytes and sperm placed in same catheter Injected directly into the fallopian tube via laparoscopy Embryo travels through the fallopian tube to the uterus for implantation Gamete Intra-Fallopian Transfer(GIFT) : Gamete Intra-Fallopian Transfer(GIFT) A mixture of a woman’s eggs and sperm are placed into the fallopian tube during a laparoscopy.
Once inserted, fertilization is allowed to occur. Zygote Intrafallopian Transfer (ZIFT) : Zygote Intrafallopian Transfer (ZIFT) Combines techniques used in IVF and GIFT Ova are placed in a petri dish with sperm If fertilization occurs, the zygote:
Is injected into fallopian tube
Travels through tube to uterus
Implants in uterus Zygote Intra-Fallopian Transfer(ZIFT) : Zygote Intra-Fallopian Transfer(ZIFT) Mixture of In Vitro Fertilization and Gamete Intra Fallopian Transfer.
Fertilization takes place outside the uterus and placed into the fallopian tubes. Cryopreservation : Cryopreservation Sperm or embryos are preserved by freezing for replacement in subsequent cycles Photo source: http://www.dcmsonline.org Intracytoplasmic Sperm Injection (ICSI) : Intracytoplasmic Sperm Injection (ICSI) A single sperm is injected directly into the cytoplasm of the oocyte
Increases probability of fertilization Genetic risk of ICSI : Genetic risk of ICSI Congenital anomaly :
Autosomal abberation: <2%
Y chromosomal abberation: 13%
not results in major anomaly other than infertility
Sex chromosomal abnormality
Higher in ICSI than natural pregnancy
1%: 47XXY, XXX, 45X, etc (Liebaers,1995)
Major malformation in Turner
Infertility obligate in Klinfelter’s synd
No major congenital handicaps
No increased rate of mental retardation IUI----intrauterine insemination : IUI----intrauterine insemination First choice for male immunological infertility IUI----intrauterine insemination : IUI----intrauterine insemination Screening criteria for ICSI or IVF option : Screening criteria for ICSI or IVF option SA sperm density Density> 20 millions
Motility>20% HBA screening HBA > 60% Sperm survival test >10 million/ml
Motility>80% <20 million?ml IVF ICSI HBA <60% If not Slide 106: Hyaluronan Acid Binding by Human Sperm:
Assessment of sperm function and sperm selection for ICSI Only live and mature motile sperm will bind to Hyaluronan The sperm plasma membrane need to be incorporated with Hyaluronan and Zona binding receptors Selecting an ART Program : Selecting an ART Program Qualifications and experience of the clinic and its personnel.
Support services available
Success rates of that specific program Conclusion : Conclusion Male infertility is multifactorial
Hormones, physiology, environment, anatomy and DNA all play a role
It is the delicate balance of all of these factors that must be weighed in order to optimize male fertility
Every evaluation is different and every treatment strategy is geared toward the individual patient and circumstance and must always take into account the female partner Lets go for a cup of tea,apne kharchey par : Lets go for a cup of tea,apne kharchey par THANKS : THANKS